Guo Yiran, Hwang Liang-Dar, Li Jiankang, Eades Jason, Yu Chung Wen, Mansfield Corrine, Burdick-Will Alexis, Chang Xiao, Chen Yulan, Duke Fujiko F, Zhang Jianguo, Fakharzadeh Steven, Fennessey Paul, Keating Brendan J, Jiang Hui, Hakonarson Hakon, Reed Danielle R, Preti George
Center for Applied Genomics, the Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Abramson Res Cntr, Ste 1016H, Philadelphia, PA, 19104, USA.
Monell Chemical Senses Center, 3500 Market St, Philadelphia, PA, 19104, USA.
BMC Med Genet. 2017 Feb 15;18(1):11. doi: 10.1186/s12881-017-0369-8.
Trimethylaminuria (TMAU) is a genetic disorder whereby people cannot convert trimethylamine (TMA) to its oxidized form (TMAO), a process that requires the liver enzyme FMO3. Loss-of-function variants in the FMO3 gene are a known cause of TMAU. In addition to the inability to metabolize TMA precursors like choline, patients often emit a characteristic odor because while TMAO is odorless, TMA has a fishy smell. The Monell Chemical Senses Center is a research institute with a program to evaluate people with odor complaints for TMAU.
Here we evaluated ten subjects by (1) odor evaluation by a trained sensory panel, (2) analysis of their urine concentration of TMA relative to TMAO before and after choline ingestion, and (3) whole exome sequencing as well as subsequent variant analysis of all ten samples to investigate the genetics of TMAU.
While all subjects reported they often emitted a fish-like odor, none had this malodor during sensory evaluation. However, all were impaired in their ability to produce >90% TMAO/TMA in their urine and thus met the criteria for TMAU. To probe for genetic causes, the exome of each subject was sequenced, and variants were filtered by genes with a known (FMO3) or expected effect on TMA metabolism function (other oxidoreductases). We filtered the remaining variants by allele frequency and predicated functional effects. We identified one subject that had a rare loss-of-function FMO3 variant and six with more common decreased-function variants. In other oxidoreductases genes, five subjects had four novel rare single-nucleotide polymorphisms as well as one rare insertion/deletion. Novel in this context means no investigators have previously linked these variants to TMAU although they are in dbSNP.
Thus, variants in genes other than FMO3 may cause TMAU and the genetic variants identified here serve as a starting point for future studies of impaired TMA metabolism.
三甲胺尿症（TMAU）是一种遗传性疾病，患者无法将三甲胺（TMA）转化为其氧化形式（TMAO），这一过程需要肝脏中的黄素单加氧酶3（FMO3）。FMO3基因功能丧失性变异是已知的TMAU病因。除了无法代谢胆碱等TMA前体物质外，患者通常会散发出一种特殊气味，因为TMAO无味，而TMA有鱼腥味。莫奈尔化学感官中心是一家研究机构，有一个项目用于评估有气味问题的人是否患有TMAU。
我们对10名受试者进行了评估，方法包括：（1）由经过训练的感官小组进行气味评估；（2）分析他们在摄入胆碱前后尿液中TMA与TMAO的浓度；（3）对所有10个样本进行全外显子组测序以及后续的变异分析，以研究TMAU的遗传学。
虽然所有受试者都报告自己经常散发出类似鱼的气味，但在感官评估中没有人有这种恶臭。然而，所有人尿液中产生>90%的TMAO/TMA的能力都受损，因此符合TMAU的标准。为了探究遗传原因，对每个受试者的外显子组进行了测序，并通过对TMA代谢功能有已知（FMO3）或预期影响的基因（其他氧化还原酶）对变异进行筛选。我们根据等位基因频率和预测的功能效应筛选了其余的变异。我们鉴定出一名受试者有罕见的FMO3功能丧失性变异，还有六名受试者有更常见的功能降低性变异。在其他氧化还原酶基因中，五名受试者有四个新的罕见单核苷酸多态性以及一个罕见的插入/缺失。在此背景下，新意味着尽管这些变异存在于单核苷酸多态性数据库（dbSNP）中，但之前没有研究人员将这些变异与TMAU联系起来。
因此，FMO3基因以外的基因变异可能导致TMAU，这里鉴定出的遗传变异为未来TMA代谢受损研究提供了一个起点。
